Last data update: May 20, 2024. (Total: 46824 publications since 2009)
Records 1-7 (of 7 Records) |
Query Trace: Krawczynski K [original query] |
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CD4+ T cells are not required for suppression of hepatitis B virus replication in the liver of vaccinated chimpanzees
Rybczynska J , Campbell K , Kamili S , Locarnini S , Krawczynski K , Walker CM . J Infect Dis 2015 213 (1) 49-56 Humans vaccinated with hepatitis B virus (HBV) surface antigen (HBsAg) sometimes develop humoral and cellular immunity to HBV proteins such as core and polymerase that are not vaccine components, providing indirect evidence that vaccine-induced immunity is not sterilizing. We previously described CD4+ T-cell immunity against HBsAg and polymerase in chimpanzees after vaccination and HBV challenge. Here, vaccinated chimpanzees with protective levels of anti-HBsAg antibodies were rechallenged with HBV after antibody-mediated CD4+ T-cell depletion. HBV DNA was detected in liver for at least 3 months after rechallenge, but virus replication was suppressed, as revealed by the absence of HBV DNA and HBsAg in serum. These observations provide direct virological evidence for nonsterilizing immunity in individuals with anti-HBsAg antibodies and are consistent with translation of HBV proteins to prime immune responses. They also indicate that CD4+ T cells were not required for suppression of HBV replication in previously vaccinated individuals. |
An outbreak of measles in an undervaccinated community
Gahr P , DeVries AS , Wallace G , Miller C , Kenyon C , Sweet K , Martin K , White K , Bagstad E , Hooker C , Krawczynski G , Boxrud D , Liu G , Stinchfield P , LeBlanc J , Hickman C , Bahta L , Barskey A , Lynfield R . Pediatrics 2014 134 (1) e220-8 Measles is readily spread to susceptible individuals, but is no longer endemic in the United States. In March 2011, measles was confirmed in a Minnesota child without travel abroad. This was the first identified case-patient of an outbreak. An investigation was initiated to determine the source, prevent transmission, and examine measles-mumps-rubella (MMR) vaccine coverage in the affected community. Investigation and response included case-patient follow-up, post-exposure prophylaxis, voluntary isolation and quarantine, and early MMR vaccine for non-immune shelter residents >6 months and <12 months of age. Vaccine coverage was assessed by using immunization information system records. Outreach to the affected community included education and support from public health, health care, and community and spiritual leaders. Twenty-one measles cases were identified. The median age was 12 months (range, 4 months to 51 years) and 14 (67%) were hospitalized (range of stay, 2-7 days). The source was a 30-month-old US-born child of Somali descent infected while visiting Kenya. Measles spread in several settings, and over 3000 individuals were exposed. Sixteen case-patients were unvaccinated; 9 of the 16 were age-eligible: 7 of the 9 had safety concerns and 6 were of Somali descent. MMR vaccine coverage among Somali children declined significantly from 2004 through 2010 starting at 91.1% in 2004 and reaching 54.0% in 2010 (chi2 for linear trend 553.79; P < .001). This was the largest measles outbreak in Minnesota in 20 years, and aggressive response likely prevented additional transmission. Measles outbreaks can occur if undervaccinated subpopulations exist. Misunderstandings about vaccine safety must be effectively addressed. |
Hepatitis C virus clearance correlates with HLA-DR expression on proliferating CD8+ T cells in immune-primed chimpanzees
Zubkova I , Duan H , Wells F , Mostowski H , Chang E , Pirollo K , Krawczynski K , Lanford R , Major M . Hepatology 2014 59 (3) 803-13 Vaccination of chimpanzees against hepatitis C virus (HCV) using T-cell-based vaccines targeting nonstructural proteins has not resulted in the same levels of control and clearance as those seen in animals reexposed after HCV clearance. We hypothesized that the outcome of infection depends on the different subtypes of activated T cells. We used multicolor flow cytometry to evaluate activation (CD38+/HLA-DR+) and proliferation (Ki67+/Bcl-2-low) profiles of CD4+ and CD8+ T cells in peripheral blood before and after challenge in chimpanzees vaccinated using DNA/adenovirus, mock-vaccinated, and chimpanzees that had spontaneously cleared infection (rechallenged). The frequencies of activated or proliferating CD8+ T cells peaked at 2 weeks postchallenge in the vaccinated and rechallenged animals, coinciding with reductions in viral titers. However, the magnitude of the responses did not correlate with outcome or sustained control of viral replication. In contrast, proliferation of the CD8+ T cells coexpressing HLA-DR either with or without CD38 expression was significantly higher at challenge in animals that rapidly cleared HCV and remained so throughout the follow-up period. CONCLUSION: Our data suggest that the appearance of proliferating HLA-DR+/CD8+ T cells can be used as a predictor of a successfully primed memory immune response against HCV and as a marker of effective vaccination in clinical trials. |
Immunopathogenesis of hepatitis E virus infection
Wedemeyer H , Rybczynska J , Pischke S , Krawczynski K . Semin Liver Dis 2013 33 (1) 71-8 The course of hepatitis E virus infection (HEV) can vary substantially between different individuals. Although most infections take a clinically silent asymptomatic course, a few patients may develop severe hepatitis that can progress to fulminant hepatic failure. In addition, cases of chronic hepatitis E have been described in immunosuppressed patients. The detailed mechanisms leading to different clinical outcomes of HEV infection are only partially understood. Both viral factors including the HEV genotype and the dose of the infectious inoculum, as well as host factors such as stage of liver disease, pregnancy or distinct genetic polymorphisms determine the course of HEV infection. Recent studies were able to associate T-cell responses, activation of the interferon system and viral evolution with severity or chronicity of hepatitis E. We here summarize the emerging data on the immunopathogenesis of HEV infection. |
Both innate and adaptive immunity mediate protective immunity against hepatitis C virus infection in chimpanzees
Barth H , Rybczynska J , Patient R , Choi Y , Sapp RK , Baumert TF , Krawczynski K , Liang TJ . Hepatology 2011 54 (4) 1135-48 Understanding the immunological correlates associated with protective immunity following hepatitis C virus (HCV) reexposure is a prerequisite for the design of effective HCV vaccines and immunotherapeutics. In this study we performed a comprehensive analysis of innate and adaptive immunity following HCV reexposure of two chimpanzees that had previously recovered from HCV-JFH1 infection. One of the chimpanzees, CH10274, became protected from active viremia by repeated challenges with homologous HCV-JFH1 and developed neutralizing antibodies, but was later infected with high-level viremia by a heterologous challenge with the HCV H77 virus that persisted for more than 1 year. The other chimpanzee, CH10273, was protected from a similar, heterologous H77 challenge without any evidence of neutralizing antibodies. Peripheral HCV-specific T-cell responses were present in both chimpanzees after challenges and, interestingly, the overall magnitude of response was lower in uninfected CH10273, which, however, exhibited a more robust CD8+ T-cell response. CH10273 showed higher hepatic expression of CD8 and CD56 (natural killer) markers than CH10274 did shortly after inoculation with H77. The heightened T-cell response was associated with an enhanced hepatic production of interferons (both type I and II) and interferon-stimulated genes (ISGs) in CH10273. Therefore, protection or clearance of HCV reinfection upon heterologous rechallenge depends on the activation of both intrahepatic innate and cellular immune responses. Furthermore, our results suggest that serum neutralizing antibodies may contribute to early control of viral replication and spread after homologous HCV rechallenges but may not be sufficient for a long-term protective immunity. CONCLUSION: Our study shows that protective immunity against HCV reinfection is orchestrated by a complex network of innate and adaptive immune responses. (HEPATOLOGY 2011;). |
Pathogenetic elements of hepatitis E and animal models of HEV infection
Krawczynski K , Meng XJ , Rybczynska J . Virus Res 2011 161 (1) 78-83 The pathogenesis of HEV infection responsible for liver pathology and clinical disease is not well understood. The main target for the virus is hepatocyte, where it replicates and is released to bile and gastrointestinal tract. Viremia is regularly seen during the virus replication. The exact mechanism of hepatocytic death is uncertain. In experimentally infected non-human primates, the peak of liver lesions, measured by alanine aminotransferase activity elevation, is concordant with the virus disappearance from stool at the time of dynamic humoral immune response; the role of cellular immunity has not been research adequately, especially HEV-specific immune response in the liver. Non-human primates (chimpanzees, rhesus and cynomolgus macaques) are most widely used animal models for the study of HEV infection, its pathogenesis and vaccine trials. Several other animal models including pigs, rabbits and chickens have recently been established for the study of various aspects of HEV infection. Infectivity studies in susceptible primates were of significance in molecular studies of the virus itself. Preclinical vaccine trials with the use of various recombinant HEV capsid proteins and viral DNA established basic platform for formulation of HEV vaccine applied in HEV-endemic regions (China, Nepal). |
Challenge pools of hepatitis C virus genotypes 1-6 prototype strains: replication fitness and pathogenicity in chimpanzees and human liver-chimeric mouse models
Bukh J , Meuleman P , Tellier R , Engle RE , Feinstone SM , Eder G , Satterfield WC , Govindarajan S , Krawczynski K , Miller RH , Leroux-Roels G , Purcell RH . J Infect Dis 2010 201 (9) 1381-9 Chimpanzees represent the only animal model for studies of the natural history of hepatitis C virus (HCV). To generate virus stocks of important HCV variants, we infected chimpanzees with HCV strains of genotypes 1-6 and determined the infectivity titer of acute-phase plasma pools in additional animals. The courses of first- and second-passage infections were similar, with early appearance of viremia, HCV RNA titers of >10(4.7) IU/mL, and development of acute hepatitis; the chronicity rate was 56%. The challenge pools had titers of 10(3)-10(5) chimpanzee infectious doses/mL. Human liver-chimeric mice developed high-titer infections after inoculation with the challenge viruses of genotypes 1-6. Inoculation studies with different doses of the genotype 1b pool suggested that a relatively high virus dose is required to consistently infect chimeric mice. The challenge pools represent a unique resource for studies of HCV molecular virology and for studies of pathogenesis, protective immunity, and vaccine efficacy in vivo. |
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